The metabolic response to high fat intake depends on dietary fatty acid composition and sex

Abstract Background/Objectives: Males and females have different propensities to develop obesity and its complications and understanding how sex affects the responds to specific nutritional signals is of great interest for developing personalized dietary interventions. Our aim was to study the impact of specific dietary lipids on energy balance and parameters of lipid metabolism in the hypothalamus and brown adipose tissue (BAT). Subjects/Methods: The metabolic responses of male and female mice to 8 weeks of diets enriched in sunflower seed oil (SSO) or palm kernel oil (PKO) were analysed. Results No change in energy intake was observed, but weight gain was induced by the fatty acid enriched diets, reaching statistical significance in response to SSO in females. The fatty acid enriched diets increased glycemia, reaching statistical significance in both sexes with SSO. In the hypothalamus citrate synthase activity was induced by both diets in both sexes, but carnitine palmitoyl transferase 1a (Cpt1a) mRNA levels increased only in females on the SSO diet. In BAT, uncoupling protein 1 and Cpt1a mRNA levels increased in both sexes with both diets, while fatty acid synthase mRNA levels decreased. Activation of p-AMPK was induced and the levels of p-mTOR decreased with both diets, although overall greater effects were observed with SSO. Conclusions Saturated and unsaturated fatty acid-enriched diets elicit distinct metabolic responses in males and females, with greater overall effects found with increased unsaturated fatty acid intake. Indeed, despite similar caloric intake, females fed the unsaturated fat-enriched diet (SSO) had greater weight gain and energy efficiency, while in BAT this was accompanied by favourable metabolic adaptations, including increased thermogenesis and fat oxidation, with less disruption of autophagy. These findings highlight the importance of diet composition and sex in shaping metabolic outcomes and emphasize the need to understand these differences when designing dietary strategies.